The major goals of the Project are to rationally design and synthesize and to determine the efficacy and safety of new vitamin D3 analogs (deltanoids). The novel deltanoids proposed here are expected to have high cancer chemoprotective and chemotherapeutic activities without causing hypercalcemia. First (Aim 1), a hybrid deltanoid will be constructed that combines the most desirable fluorine atom substitution pattern of Hoffman- LaRoche's popular and potent deltanoid Ro 24-5531 with our deltanoid QW 1624F2-2. Such a new side-chain polyfluorinated deltanoid is expected to have a therapeutic profile superior to that of either of its parent deltanoids. Because some of our conceptually new sulfone deltanoids are potent and safe (i.e. non-calcemic) at inhibiting DMBA-induced skin tumorigenesis in mice, a series of new sulfone deltanoids (Aim 2) will be prepared in which small, rational structural changes (e.g. 16- substitution) will force the deltanoid side-chain into a northwest orientation that is expected to raise chemoprotective potency without causing hypercalcemia. Also, a few sulfone deltanoid dimers (Aim 3) will be prepared as molecular probes to study the effect of such chemical inducers of receptor dimerization on intracellular signal transduction processes. Additionally, a series of A-ring 2,2-disbustituted deltanoids (Aim 4) will be prepared incorporating 2,2-dimethyland 2,2- difluoro substituents that are expected sterically and electronically to retard metabolism at the 1- and 3-OH positions, thereby increasing the biological lifetime and efficacy of these new deltanoids. The most promising of these new antiproliferative but non-calcemic deltanoids will be synthesized on 15-30 mg scale for cancer chemoprevention and chemotherapy testing in animals with focus on skin and breast cancers (Aim 5). Collectively, these studies will provide important structure- activity insights into the cancer chemoprotective and chemotherapeutic actions and molecular biology of vitamin D3 analogs.